Table 1.

Selected experimental and clinical findings associated with LCN2 in cancer models, tissues, and cell lines.

Type of Cancer	LCN2 Expression	Model	Major Findings	Function of LCN2	References
Adeno- carcinoma	upregulated	A549 cells and MCF7 cells treated with MK886	Apoptosis induced by treatment with MCF7 was accompanied by a dose- and time-dependent increase of LCN2 mRNA levels	Data indicate that, although the induction of LCN2 correlates with apoptosis, induction represents a survival response	[65]
Thyroid	upregulated	siRNA knockdown in FRO cell line	LCN2 knockdown blocks the ability of FRO cells to form colonies in soft agar and tumours in nude mice and induces apoptosis	LCN2 is a survival factor for thyroid neoplastic cells. Data suggests that NF-κB contributes to thyroid tumour cell survival by controlling iron uptake via LCN2	[60]
Breast	upregulated in tissue and urine	Breast cancer cell lines MCF-7 and MDA-MB-231 transfected with siRNA: Overexpression study on the same cell lines	Overexpression of LCN2 leads to an increase in mesenchymal factors (vimentin and fibronectin) and decrease in epithelial (E-cadherin). Silencing inhibits cell migration and reduces ER-α expression MCF-7 tumours revealed that the LCN2-overexpressing ones exhibited increased growth rates that were accompanied by increased levels of MMP-9, increased angiogenesis, and an increase in the tumour cell proliferative fraction	LCN2 promotes breast cancer progression LCN2-MMP-9 complex is facilitating angiogenesis and tumour growth	[59,70]
Esophageal	upregulated	EC109, SHEE, SHEEC, EC8712, KYSE150, KYSE180, and TE3 cell lines	LCN2 increases MMP-9 and phospho-ERM (phospho-ezrin/radixin/moesin), decreases phospho-cofilin and cytoskeleton F-actin rearrangement in oesophageal squamous cell carcinoma cells	LCN2 promotes the migration and invasion of oesophageal squamous cell carcinoma cells through the ERK1/2 pathway	[68]
Ovary	upregulated	HEY, PEO.36, SKOV3, OVCA433, and OVHS1 cell lines	Downregulation of LCN2 expression correlates with the upregulation of vimentin expression, enhanced cell dispersion, and downregulation of E-cadherin expression	LCN2 is associated with an epidermal growth factor that induced EMT	[63]
Endometrium	high expression of LCN2 and vascular endothelial growth factor (VEGF), high LCN2 serum levels in cancer patients	HHUA and RL95-2, and LCN2-low-expressing cell line HEC1B	Effects of LCN2 silencing on cell migration, cell viability, and apoptosis under various stresses, including ultraviolet irradiation and cisplatin treatment	LCN2 was involved in the migration and survival of endometrial carcinoma cells under various stresses in an iron-dependent manner. The survival function of LCN2 may be exerted through the PI3K pathway and suppression of the p53-p21 pathway	[62]
Colon	upregulated	SW620-OB, SW620-LCN2 (5 × 106), SW480-SHB, and SW480-sh-LCN2 cells were inoculated subcutaneously into the BALB/c nude mice Knockdown of LCN2 using siRNA in colecteral cancer cells (CRC) cells LCN2 overexpression or antisense LCN2	LCN2 blocked cell proliferation, migration and invasion in vitro and in vivo, and inhibited translocation of NF-κB into the nucleus LCN2 negatively modulated proliferation, EMT, and energy metabolism in CRC cells Overexpression altered subcellular localization of E-cadherin and catenins, decreased E-cadherin-mediated cell-cell adhesion, enhanced cell-matrix attachment, and increased cell motility and in vitro invasion. Silencing aggregated a growth pattern and decreased in vitro invasion. These effects were mediated through the alteration of the subcellular localization of Rac1	LCN2 suppresses metastasis of colorectal cancer LCN2 negatively regulates cell proliferation and EMT through changing metabolic gene expression in colorectal cancer increasing proliferation and metastasis LCN2 decreases E-cadherin-mediated cell-cell adhesion and increases cell motility and invasion	[61,71]
Lung	upregulated	Downregulation by shRNA Knockdown by siRNA in lung cancer cell line A549	Depletion of LCN2 expression decreased the ability of cell proliferation and induced cell apoptosis The radiosensitivity of these cells was enhanced	Downregulation of LCN2 suppresses the growth of human lung adenocarcinoma through oxidative stress involving Nrf2/HO-1 signalling LCN2 increases lung cancer cells radio-resistance	[64,65]
Chronic Myeloid Leukemia	upregulated	LCN2 mRNA in blood samples and protein in sera	A highly significant increase of mRNA expression and protein secretion was shown in patients at diagnosis	LCN2 play an important role in the physiopathology of CML	[66]
Oral	significantly downregulated in primary malignant and metastatic tissue	shRNA-mediated knockdown of LCN2 was carried out in the SAS cell line	Knockdown increased oral cancer cell proliferation, survival, and migration. Silencing of LCN2 activated mTOR signalling and reduced autophagy.	Downregulation of LCN2 activates the mTOR pathway and helps in the progression of oral cancer. Silencing of LCN2 increases oral cancer cell proliferation and survival Levels of LCN2 and the LCN2/MMP-9 complex may be useful in non-invasively monitoring OSCC progression and migration	[69,72]
Kidney	upregulated	CAKI 1, 786-O, A498, and RCC4 cell lines were subjected to treatment with iron free or loaded LCN2	Iron-free LCN2 reduced migration and matrix adhesion. In contrast, stimulation with iron loaded LCN2 enhanced migration and adhesion.	Iron load defines the pro-tumour characteristics of LCN2 in renal cancer	[73]
Pancreatic	high in serum (ELISA) and tumour tissue	LCN2 overexpression in pancreatic cell lines. Cells were subsequently injected into the subcapsular region of the nude mice pancreas. LCN2 expression was downregulated by shRNA in pancreatic ductal adenocarcinoma cells (BxPC3 and HPAF-II); overexpression of LCN2 in the same cell lines	LCN2 overexpression (MIAPaCa-2 and PANC-1) significantly blocked cell adhesion and invasion in vitro, reduced Focal adhesion kinase (FAK) phosphorylation, potently decreased angiogenesis in vitro partly through reduced VEGF production Downregulation significantly reduced attachment, invasion, and tumour growth in vivo. The opposite results were found by LCN2 overexpression.	LCN2 acts as suppressor of invasion by suppressing FAK activation and inhibits angiogenesis partly by blocking VEGF LCN2 plays an important role in the malignant progression of pancreatic ductal carcinoma	[11]
Gastric	high in tumour tissue and serum	LCN2 gene silencing in MGC-803 and SGC-7901 cells by LCN2-siRNA; cells were subsequently used for xenograft model in nude mice MGC-803 cells were treated with siRNA against LCN2 and also implanted into nude mice	The mice experiment showed that LCN2 gene silencing inhibited the proliferation and tumorigenicity of the MGC-803 and SGC-79 LCN2-siRNA cells exhibited inhibited proliferation, enhanced apoptosis, decreased expressions of NF-κB and Bcl- 2. Respective cells showed repressed tumorigenicity in vivo.	LCN2 gene silencing inhibits proliferation and promotes apoptosis of human gastric cancer cells LCN2 gene silencing inhibits proliferation and promotes apoptosis of MGC-803 cells	[74,75]
Prostate	high in tumour tissue and cell lines	LCN2 knockdown in prostate cancer cells (PC3, DU145) by shRNA	Knockdown of LCN2 suppresses growth and invasion of prostate cancer cells	LCN2 might play an important role in regulation of proliferation and invasion of human prostate cancer	[76]
Cholangio- carcinoma (CCA)	upregulated	Human RMCCA-1 cell line subjected to LCN2 downregulation by siRNA Human CCA cell lines were subjected to LCN2 knockdown and overexpression	LCN2 knockdown suppressed invasion by reducing LCN2/MMP-9 complex formation LCN2 knockdown inhibited CCA cell growth in vitro and in vivo through induction of the cell cycle arrest at G0/G1 phases and repression of EMT; overexpression of LCN2 in CCA cells increases cell metastatic potential	LCN2 promotes the invasiveness of the cholangiocarcinoma cells by forming a complex with MMP-9 LCN2 is a promising target for CCA treatment and bile LCN2 level is a potential diagnostic marker for CCA	[77,78]